Chapter 2. The Total Carbohydrate Burden & Individual Vulnerability

We welcome your use of this resource but please cite:

PSGRNZ (2026) Reclaiming Health: Reversal, Remission & Rewiring. Understanding & Addressing the Primary Drivers of New Zealand’s Metabolic & Mental Health Crisis. Bruning, J.R., Physicians & Scientists for Global Responsibility New Zealand. ISBN 978-1-0670678-2-3

This Reclaiming Health paper places a strong emphasis on cumulative carbohydrate burdens, because a growing body of international scientific and clinical literature identifies excess dietary carbohydrate intake of moderately processed and refined carbohydrates as a central driver of metabolic syndrome. Strong evidence suggests that this pattern has been reinforced by dietary guidelines that have historically encouraged carbohydrate consumption while understating the role of healthy fats and proteins.

As outlined in the Reform section, a key opportunity lies in recalibrating dietary guidelines to bring fats and proteins back into public view, alongside the integration of health coaching and substantial reinvestment in nutrition education. This would represent a shift away from guideline frameworks primarily designed to prevent nutrient deficiency toward approaches which may support satiety, appetite regulation, and metabolic stability, optimise metabolic health across the life course, and reduce risk for obesity.

Importantly, the paper does not argue that obesity is driven exclusively by carbohydrate intake. Excess energy consumption can and does contribute to weight gain. Rather, Reclaiming Health situates carbohydrate exposure within a broader scientific landscape. Multiple models seek to explain obesity pathogenesis. These include the energy balance model (EBM), the carbohydrate-insulin model (CIM), [1] and the more recently articulated REDOX model. [2] Taken together, the EBM, CIM and REDOX models offer complementary insights into the pathophysiology of obesity, rather than mutually exclusive explanations.

The EBM posits that changes in food environments, particularly the widespread availability and aggressive marketing of inexpensive, energy-dense, ultra-processed, and highly palatable foods, have driven obesity by increasing consumption beyond physiological energy requirements. Foods that are low in fibre and protein and offered in large portion sizes are thought to disrupt neural satiety signalling. The EBM highlights that external food-related cues, and the properties of the foods themselves, disrupt healthy neural signalling, and result in excess consumption and promoting excess accumulation of body fat. [3]

By contrast, the carbohydrate–insulin model (CIM) of obesity metabolic consequences of diets that are predominantly high in refined, rapidly digestible carbohydrate-containing foods, including fructose rich foods and beverages. This model proposes that such diets alter fuel partitioning, directing energy substrates away from oxidation and toward storage in adipose and other tissues, thereby promoting fat accumulation even in the absence of overt caloric excess.[4]

The REDOX model adds a further layer of explanation, proposing that obesity may arise from disturbances in cellular and systemic redox balance. Altered oxidation–reduction signalling can disrupt metabolic and hormonal regulation, interfere with insulin action and energy sensing, and impair adipose tissue function. In this framework, obesity emerges from perturbed signalling and feedback mechanisms shaped by environmental, dietary, and metabolic exposures, rather than from caloric excess alone. [5]

PSGRNZ’s emphasis on the carbohydrate-insulin model is not driven solely by obesity pathophysiology, but by the breadth of evidence linking excess carbohydrate intake to elevated insulin, triglycerides, blood pressure, and adverse mental-health outcomes. Accordingly, Reclaiming Health differs from conventional approaches by drawing on mechanistic studies alongside case series, cohort data, and real-world clinical evidence to illustrate the multifactorial nature of metabolic and mental ill-health. Obesity may precede the other markers of metabolic syndrome, but in many cases, the other markers precede obesity.

The paper also highlights an under-examined dimension: addictive eating patterns associated with cumulative refined carbohydrate exposure, including but not limited to ultra-processed foods. These patterns contribute substantially to non-adherence to dietary guidelines, often precede metabolic syndrome and obesity, yet remain poorly integrated into academic and policy frameworks. While fats and proteins have been progressively marginalised within dietary guidance, the EBM model of obesity offers limited insight into how individuals might sustainably manage hunger and satiety through caloric restriction, particularly in the presence of glycaemic volatility and reward-driven, addictive eating behaviours.

While there is sound scientific evidence supporting greater regulation of sugar, defaulting to an exclusive focus on ultra-processed foods (UPFs) as a discrete regulatory target risks creating a political quagmire, as not all UPFs are addictive.

As such, many of the recommendations for reform, outlined in Chapter 12, extend well beyond an individual-level approach. The proposed pathways for reform are intended to improve key metabolic parameters that increase risk across a spectrum of metabolic and mental health conditions. Evidence examined in the paper suggests that the approaches set out in the Reform section can deliver substantial metabolic and health benefits, again with particularly strong effects in lower-income populations.

PSGRNZ’s recommendations involve structural changes designed to support dietary transition across New Zealand. The evidence reviewed indicates that these approaches deliver significant gains, particularly among lower-income groups.

The Carbohydrate-Insulin Model.

Nearly two billion people worldwide are now overweight or obese. [6] The conventional understanding holds that obesity drives type 2 diabetes mellitus (T2DM), and that together, these conditions set off a cascade of risks for a striking array of diseases and syndromes. In practice, insulin resistance develops first in obese and non-obese people. Beta cells are then unable to compensate.[7] However, as New Zealand doctors reversing diabetes have found, beta cell ‘relative’ failure is rare. Their experience aligns with other research which shows that pancreatic beta cell function and insulin secretion improves with dietary shifts.[8]

When eaten in quantities that exceed immediate energy demands and glycogen storage capacity, starchy carbohydrates are readily converted into body fat, fuelling weight gain and metabolic strain. An increasing range of randomised control trials support the suggestion that reductions in carbohydrate rather than low-fat intakes, may be more strongly associated with weight loss and reduction in risk for obesity.[9]

Dietary carbohydrates include sugars and starches, both of which are ultimately broken down in the digestive tract by enzymes into their simplest form, glucose. Starches vary in their digestibility: they may be rapidly digestible, slowly digestible, or resistant to digestion, and their characteristics can be significantly altered by domestic cooking methods and industrial processing. As with sugars, excessive consumption of rapidly digestible starches is associated with adverse health outcomes. Understanding differences in starch digestibility, and how quickly blood glucose levels rise after consuming starchy foods, is an important aspect of public health.[10]

The resultant glucose is absorbed into the bloodstream, raising blood sugar levels (reflected in HbA1c over time). In response, the pancreas releases insulin, a hormone that signals cells to take up glucose for immediate use or storage. Muscle and other body tissues use glucose as a rapid fuel source, particularly during physical activity, while liver and muscle cells store excess glucose as glycogen, a compact and readily mobilised energy reserve.

However, the body’s glycogen storage capacity is limited. Once these reserves are full, continued high glucose availability, especially from carbohydrate-based meals and snacks, triggers the liver to convert excess glucose into fatty acids through a process known as de novo lipogenesis (DNL). These fatty acids are combined with glycerol to form triglycerides, which are packaged by the liver into very-low-density lipoproteins (VLDL) and released into the bloodstream for transport as energy.

Triglycerides in the bloodstream are a normal component of metabolism, serving as a transport form of fat for energy use or storage. After a meal, dietary fats are absorbed by intestinal cells and packaged into chylomicrons, large, triglyceride-rich lipoprotein particles that enter the circulation via the lymphatic system. At the same time, the liver produces VLDL to carry triglycerides synthesised from excess carbohydrate or protein. These particles circulate through the bloodstream, where triglycerides may be delivered to adipose tissue for long-term storage as body fat or utilised by muscle tissue as an alternative energy source when required.[11] [12] [13] [14]

Summary papers addressing the physiological role of VLDL are scarce. Normal physiological function is typically treated as background knowledge and not considered worthy of synthesis. Journals, funding bodies, and regulators have historically prioritised disease endpoints, hazard identification, and modifiable risk factors. In physiological terms, VLDL secretion is a normal and essential hepatic function that protects hepatocytes from lipid overload, distributes endogenously synthesised energy substrates to peripheral tissues, and supports cellular membrane integrity and mitochondrial function; pathology arises primarily from chronic dysregulation of VLDL production and clearance rather than from VLDL itself.

VLDL is upstream of low-density lipoproteins (LDL). LDL is largely a metabolic product of VLDL following triglyceride removal. LDL play important physiological roles that are often downplayed. The primary cargo of LDL is cholesterol, and its principal physiological function is to deliver cholesterol for incorporation into cell membranes, synthesis of steroid hormones and bile acids, and support of myelin and synaptic function. There is no fixed biological amount of cholesterol per LDL particle and LDL particles vary widely in size and cholesterol content. An excess LDL burden will often reflect upstream VLDL dysregulation rather than a primary cholesterol excess.

The physiological roles of VLDL and LDL described here are foundational to lipid biochemistry and human metabolism and are widely accepted in the scientific literature; however, contemporary reviews overwhelmingly frame these lipoproteins through disease-risk paradigms rather than synthesising their normal biological functions.

Both injected insulin and pancreas-derived insulin promote the transport of triglycerides from the bloodstream into tissues, predominantly adipose tissue, even when the original dietary source is carbohydrate rather than fat. The precise mechanisms remain incompletely understood.

Insulin, the master regulator of energy metabolism, is central to this process. Insulin not only lowers blood glucose by facilitating its uptake, insulin also promotes fat storage by encouraging triglyceride uptake into fat cells, inhibiting fat breakdown. Under healthy conditions, this clearance is efficient, and triglyceride-rich lipoproteins do not remain elevated for long.

Over time, consistently high carbohydrate intakes, particularly from refined, high-glycaemic sources, can lead to chronically elevated compensatory insulin levels (hyperinsulinaemia), increased circulating triglycerides, and progressive fat accumulation. If carbohydrate intake (and thus hyperinsulinaemia) is not meaningfully reduced, this process can continue until pancreatic insulin secretion becomes impaired, resulting in persistently elevated blood glucose (HbA1c) and triglyceride levels.

As circulating triglyceride concentrations rise, the risk and severity of poorly controlled type 2 diabetes mellitus (T2DM) increase, alongside heightened risk of atherosclerotic disease, arterial occlusion, and myocardial infarction.[15] [16] Scientists have increasingly questioned the marginal benefits of many cholesterol-lowering drugs when cholesterol is treated as a surrogate marker for cardiovascular disease (CVD). In contrast, sustained elevations in blood glucose and insulin typically precede, and contribute to, rising triglyceride concentrations, increasing risk for both CVD and diabetes.[17]

A substantial and growing body of research indicates that glycaemic instability, insulin resistance, compensatory hyperinsulinemia, and associated low-grade inflammation underpin much of the contemporary burden of chronic disease. Together, these processes drive progressive metabolic dysfunction and neurodegeneration, limiting the ability of individuals and families to achieve and sustain optimal health. Pathophysiological injury begins at the mitochondrial level, where impaired mitochondrial function disrupts cellular energy production, increases oxidative stress, and propagates metabolic dysfunction across insulin-sensitive tissues.[18]

Genome-wide association studies have indicated that more than 65 genes are associated with an elevated risk of T2DM. These genes are involved in regulating the metabolic pathways of glucose homeostasis, insulin signalling, and sensitivity.[19] Generic dietary recommendations may be unsuitable for people with these genes, and such groups may benefit from dietary approaches that shield them from over-consumption of refined carbohydrates.

Some people (for example many South Asian populations) develop type 2 diabetes mellitus (T2DM) at a lower body mass index (BMI) and at lower levels of apparent adiposity than other groups.[20] People differ (including by ancestry) in how much subcutaneous fat they can safely store before ‘spillover’ to liver, pancreas, and muscle (ectopic fat) drives insulin resistance.[21] [22] [23]

When modern diets high in refined carbohydrates intersect with these biological differences, the tipping point into metabolic disease can be reached more rapidly. Health scholars have proposed that cutoff values for BMI may need to be revised to due to the risk that the current recommendations for obesity under-recognise the risk of developing T2DM in minority ethnic populations.[24]

Complementary interventions alongside dietary changes may further support the lowering of blood glucose. Dr Alpana Shukla has led trials on meal sequencing (also called food order, carbohydrate-last eating, or nutrient pre-loading) to control post-prandial blood glucose and insulin responses.[25] Time restricted eating (or fasting) in conjunction with a low carbohydrate diet is increasingly supported by studies[26] [27] [28], however, consideration needs to be given to the challenges inherent in transitioning to a fasted state and the intersecting challenge of food addiction (discussed in later chapters).

These processes also exert a distinct intergenerational impact. Infants born to mothers with T2DM or elevated insulin levels during pregnancy are more likely to be large for gestational age and to have increased adiposity at birth. Excess maternal glucose readily crosses the placenta, stimulating the foetal pancreas to increase insulin secretion. In the foetus, insulin functions as a potent growth factor, promoting accelerated growth and increased fat deposition. Although maternal insulin itself does not cross the placenta, maternal insulin resistance enhances placental transfer of glucose and lipids, indirectly driving foetal hyperinsulinaemia and adiposity, effectively acting as a metabolic amplifier across generations.[29] [30] [31]

An increasing range of studies, from mechanistic and biomarker studies to case studies and trials provide firm scientific evidence for carbohydrates as a primary driver of obesity and metabolic disease via this insulin pathway, rather than the historic consensus position that calorific consumption is the primary driver of obesity.[32] [33] A simple focus on calorie restriction may not be the most effective approach for reducing risk parameters when the carbohydrate-insulin pathway is taken into consideration.[34] Relatedly, most calorie-related research and policy does not address craving and food-addiction-related issues and the role of satiety and the regulation of appetite, when addressing dietary behaviour and health.

Insulin resistance is not driven by excess carbohydrate intake alone. Factors such as chronic stress, elevated cortisol and epinephrine, inadequate or disrupted sleep, exposure to environmental chemicals, and certain medications can contribute to the development of insulin resistance.

Metabolic Syndrome & Type Two Diabetes Mellitus (T2DM).

A growing scientific literature consistently associates insulin resistance and hyperinsulinaemia with a range of conditions that are increasingly prevalent in modern societies, including type 2 diabetes mellitus, cardiovascular disease, cellular senescence and cancer[35], and neurodegenerative diseases. [36] [37] [38] [39]
Metabolic syndrome describes a cluster of interrelated conditions: including hypertension, dyslipidaemia, obesity, type 2 diabetes mellitus, and chronic inflammation, that share common underlying mechanisms. The carbohydrate–insulin pathway represents a central mechanistic axis influencing the development and progression of metabolic syndrome.

Figure 2. Fazio S, Fazio V, Affuso F. The link between insulin resistance, hyperinsulinemia and increased mortality risk. Academia.

Hyperinsulinaemia, insulin resistance, and impaired metabolic function often precede a broad spectrum of inflammatory, metabolic, and brain-related conditions, contributing to microvascular dysfunction and increasing the risk of cardiovascular disease[40], cancer, visual impairment[41] [42] [43], neurodegeneration[44], and premature mortality. [45] [46] [47] Clinical features commonly associated with insulin resistance include acanthosis nigricans, metabolic-associated fatty liver disease (MAFLD), hyperandrogenism in females, and polycystic ovary syndrome (PCOS).[48]

People consuming diets high in sugars, refined carbohydrates, and ultra-processed foods are at increased risk of developing overlapping features of metabolic syndrome alongside a range of brain-related conditions.[49] [50] [51] An appreciation of the carbohydrate–insulin pathway helps explain why carbohydrate quality, quantity, and timing are critical not only for glycaemic control, but also for lipid regulation, adiposity, and overall metabolic health. [52] [53] [54]

T2DM is diagnosed when HbA1c is ≥ 50 mmol/L or fasting glucose is ≥ 7 mmol/L in repeated tests. Prediabetes is diagnosed when HbA1c is between 41 – 49 mmol/mol or fasting glucose 6.1 – 6.9 mmol/L or 2-hour glucose on GTT 7.8 – 11 mmol/L. [55] People with type 1 diabetes mellitus (T1DM) must contend with a pancreas that does not work, i.e. secrete insulin.

T2DM constitutes up to 96% of diabetes cases globally. A 2021 The Lancet analysis reported that more than 90% of the age-standardised diabetes prevalence rate across major regions was due to type 2 diabetes.[56]

T2DM is increasing in prevalence. Current New Zealand data on diabetes is based on estimates held with the Virtual Diabetes Register (VDR). In 2024, about 348,500 people were estimated to have diabetes in Aotearoa New Zealand. The estimated age-standardised prevalence of diabetes has increased from 36.6 (in 2013) to 47.0 per 1000 population, with the highest prevalence in Pasifika (137.2 per 1000 Pasifika population), Indian (103.6 per 1000 Indian population) and Māori (82.4 per 1000 Māori population) communities.[57] The register does not discern between T1DM and T2DM, nor does it disclose shifts in prevalence by age group over time.

It is that thought that the prevalence of diabetes has been increasing by 7% per year.[58] A 2025 paper calculated that:

Aotearoa New Zealand will experience a significant increase in the absolute volume of prevalent diabetes, rising by nearly 90% to more than 500,000 by 2044. The age-standardised prevalence of diabetes will increase from around 3.9% of the population (268,248) to 5.0% overall (502,358). The prevalence and volume of diabetes diagnoses will increase most drastically for Pacific peoples, most notably Pacific females for whom diabetes prevalence is projected to increase to 17% of the population by 2044.[59]

The current annual cost of T2DM in New Zealand is estimated to be $2.1 billion. PWC calculated that the annual cost would increase by 63% to $3.5 billion in the next 20 years.[60] PWC drew attention to the additive costs of a diagnosis in youth:

the personal and economic impact of the disease is most detrimental when a person is diagnosed early in life. When comparing the lifetime cost of someone diagnosed with type 2 diabetes at age 25 years ($565k) to the lifetime cost of someone diagnosed at age 75 years ($44k), the cost differential is $521k or a factor of 13. This is significant given the shift towards younger cohorts of New Zealanders developing type 2 diabetes. [61]

Coronary Artery / Heart Disease Risk.

Cardiovascular risk is only one aspect of the broader metabolic risk landscape. Coronary artery disease (a form of cardiovascular disease) occurs when these processes take place within the coronary arteries supplying the heart.

A diagnosis of T2DM represents the tip of a ‘risk iceberg’, signalling a spectrum of disease risks that stem from chronically elevated HbA1c and triglyceride levels, including vascular, renal, hepatic, and neurological complications. An increasing range of studies consistently demonstrate that carbohydrate restrictive diets improve cardiovascular health, reducing triglyceride levels, blood pressure and other inflammatory markers.[62]

A high triglyceride-to-high-density lipoprotein ratio predicts cardiovascular risk and is a recognised surrogate marker of insulin resistance. This ratio often improves rapidly with carbohydrate reduction. By contrast, low-density lipoprotein cholesterol (LDL-C), the cholesterol content within LDL particles, does not reliably reflect cardiometabolic risk in isolation and may poorly predict cardiovascular disease in the presence of insulin resistance and metabolic dysfunction. Individuals with identical LDL-C values can have markedly different particle numbers and risk profiles, which helps explain why LDL-C often tracks poorly with outcomes when insulin resistance and inflammation are present.

Cardiac problems arise when triglycerides remain chronically elevated due to excessive production (often from high carbohydrate diets, insulin resistance, or liver overactivity) or impaired clearance (as in metabolic syndrome or genetic lipid disorders). Persistently high triglycerides mean a constant presence of triglyceride-rich lipoproteins and their remnants in circulation. These remnants are particularly dangerous because they can penetrate the arterial wall, where they contribute to the build-up of atherosclerotic plaque.

The heart disease risk grows as fatty deposits in the blood (atheroma) attach to artery walls which over time, become hardened and stiff. In the arterial wall, remnants are taken up by macrophages, forming lipid-laden ‘foam cells’. Over time, this accumulation of fat, cholesterol, and inflammatory cells creates plaques that narrow and stiffen arteries, a process called atherosclerosis. Triglyceride-rich particles also promote low-grade inflammation, oxidative stress, and endothelial dysfunction (damage to the artery’s inner lining), all of which accelerate plaque growth and instability.

Unstable atherosclerotic plaques can rupture, exposing their lipid-rich contents to the bloodstream and triggering clot formation (thrombosis). If such a clot develops in a coronary artery, it can abruptly block blood flow to part of the heart muscle, resulting in a myocardial infarction (heart attack).

Elevated triglycerides are not merely markers of metabolic imbalance; they actively contribute to the pathological cascade underlying coronary artery disease. Triglycerides and blood pressure rise in parallel because they share upstream metabolic drivers, particularly insulin resistance, endothelial dysfunction, and vascular inflammation. Managing triglycerides is therefore a central component of cardiovascular risk reduction, alongside controlling blood pressure, blood glucose, and insulin instability.

Saturated Fats and Cholesterol – guilty by association?

Cholesterol has been used as a surrogate target for the prevention of heart disease. The heart-disease hypothesis postulates that reducing dietary saturated fat lowers serum cholesterol, thereby reducing cardiovascular risk. [63] Keeping LDL-C low by restricting saturated fat was an underpinning rationale for low-fat and low-saturated-fat diets. Carbohydrate-restricted diets may be associated with higher cholesterol levels but typically occur in a context of otherwise low metabolic risk.[64] [65]

New Zealand’s dietary guidelines directly influence the scope and framing of the questions officials include in national dietary surveys. A New Zealand Ministry of Health report, Adults’ Dietary Habits (2022), illustrates the Ministry’s disproportionate emphasis on dietary fat reduction, alongside a relative lack of attention to adequate protein intake and an absence of consideration of cumulative carbohydrate intake.

The report refers to ‘fat’ fifty-seven times predominantly in the context of promoting low-fat alternatives, while ‘protein’ is mentioned only three times, each instance limited to noting that nuts, seeds, and legumes are protein sources, with no discussion of animal-derived protein. The carbohydrate macronutrient class is not discussed at all. In addition, no differentiation is made between vegetable classes (for example, starchy vegetables such as potatoes versus leafy green vegetables such as silverbeet), and total daily protein intake is not estimated or reported. [66]

Insulin is a tiny but highly potent molecule, while cholesterol is a much larger molecule. Gary Taubes meticulous research has shed light on why and how the more easily detectable cholesterol created the heart disease risk, while the invisible insulin was neglected. [67] Contemporary beliefs that cholesterol is the driving factor for heart disease risk, rather than carbohydrate-mediated lipidosis (high triglyceride levels), may be a consequence of the limitation of early testing technologies and later studies which may have exaggerated the relationship of high cholesterol with mortality risk. [68]

This was the origin of the belief that high saturated-fat diets contribute to heart disease risk. It wasn’t until after 1960 that researchers would appreciate how insulin levels in individuals with T2DM would spike far higher than that of healthy populations after consuming carbohydrates.[69]

Reviews consistently highlight the lack of robust evidence supporting an association between saturated fat intake and adverse cardiovascular outcomes, emphasising inconsistent findings and the context-dependent nature of reported effects.[70] [71] [72] [73]

In 2014 a U.K. based group assessed the relative risk of consumption of saturated, monosaturated, and polyunsaturated fats. The group concluded:

Current evidence does not clearly support cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of total saturated fats.[74]

In A 2015 review identified that saturated fats were not associated with all-cause mortality, CVD, CHD, ischemic stroke, or T2DM, while finding that trans fats were associated with all-cause mortality, total CHD, and CHD mortality.[75] A later Cochrane review (2015, updated 2020) determined that reducing saturated fat intake for at least two years causes a potentially important reduction in combined cardiovascular events.[76] New Zealand researchers evaluated that review, finding that the relative risk became non-significant when using more robust assumptions. [77]

Two 2025 reviews have further confirmed the absence of convincing evidence implicating saturated fat in cardiovascular disease. Steen et al. found only low to moderate certainty, i.e. no significant evidence that that reducing saturated fat intake might reduce risk for at-risk groups. For people with low baseline risk, absolute reductions were below the threshold of importance.[78] Yamada et al. concluded that:

The findings indicate that a reduction in saturated fats cannot be recommended at present to prevent cardiovascular diseases and mortality. [79]

Studies may fail to adequately control for dietary fat quality and carbohydrate burdens, which may act as significant confounders of outcomes.[80] The health effects of fats depend not just on their type (saturated, monounsaturated, polyunsaturated), but on the extent of processing and refining. Unprocessed or minimally processed fats, such as those found in extra virgin olive oil, nuts, seeds, avocados, and oily fish, consistently show protective effects for heart and metabolic health. Evidence also suggests that replacing refined carbohydrates with unprocessed fats yields better outcomes than simply reducing fat intake.

The example of eggs illustrates how public health messaging can become misdirected. From the 1970s through the early 1990s, dietary cholesterol was widely portrayed as a driver of elevated blood cholesterol, and eggs were framed as directly harmful to heart health. These restrictions peaked in the 1980s and early 1990s, before being revised as evidence showed that dietary cholesterol has only a modest and variable effect on serum cholesterol and cardiovascular risk; however, the associated cultural risk perception has persisted. More recent evidence increasingly highlights the nutritional value of eggs, with a large Australian cohort study of older adults finding that frequent egg consumption was associated with a lower risk of cardiovascular disease and all-cause mortality.[81]

Cholesterol is a sterol (lipid) that plays metabolic key roles, including cell signalling and hormone synthesis. Cholesterol is present in all vertebrates, while most invertebrates (including insects, molluscs and crustaceans) do not synthesize cholesterol but source it from their diet.[82] [83] This fundamental role of cholesterol across all systems suggests that early diagnostic testing for plaque in sclerotic arteries would naturally, consistently detect elevated cholesterol levels. This did not mean that cholesterol was the driver of heart disease.

Cholesterol is synthesized from acetyl-CoA in a multi-step pathway and cholesterol is most concentrated in organs involved in membrane biogenesis, hormone synthesis, cellular signalling and lipoprotein assembly. Lipoproteins are the shipping containers that carry cholesterol to where it is required.[84] The membrane of every cell requires cholesterol to make and maintain them. The liver controls homeostasis, and the main sites are in the liver, intestine and brain but the adrenal glands, gonads, skin, kidney, lungs, spleen and muscle can also synthesise cholesterol.[85] [86] [87] [88] [89]

Cholesterol’s fundamental role in the brain is well established. Cholesterol is the major building block of myelin sheaths and cholesterol is essential to maintain its compact structure. Cholesterol is crucial for synapse formation and function, influencing neurotransmitter release and receptor organisation, and hence plays a key role in plays a central role in early brain development.[90] [91] [92]

Higher HDL-cholesterol is associated with greater longevity.[93] Low low-density lipoprotein cholesterol (for example below 70 mg/dL) may be associated with health risks including mortality while high levels (such as over 200 mg/dL) may be health promoting.[94] [95]

Statins are HMG-COA reductive inhibitors and are taken to reduce cholesterol levels, with the impression that this will reduce cardiovascular-related mortality. However, primary and secondary prevention trials suggest that the median postponement of death for may be only 3.2 and 4.1 days, respectively.[96] Statins may be associated with reduced cholesterol levels that are detrimental to brain health. Trials that failed to demonstrate that by lowering cholesterol coronary heart disease would be prevented, may have been downplayed,[97] excluded and suppressed.[98] Animal studies have revealed that statins can lower cholesterol levels in the brain.[99] [100] [101]

The Inflammatory Cascade that Drives Multimorbidity, & High Sensitivity C-reactive Protein.

Inflammation can be provoked by an acute injury, or accrue slowly over time from toxic exposures which, if they occurred rarely, would not build up to inflammation at the system level, whether an organ, tissue or a whole-body response.

Persistent high refined carbohydrate exposures drive inflammation in the body. As the cascade diagram below shows, it does not happen all at once but builds over time. The cascade occurs from a convergence of hyperinsulinemia, glycaemic volatility, ectopic fat accumulation, adipocyte stress and macrophage infiltration. [102] [103] [104]

High blood glucose (hyperglycaemia) is toxic to cells and to the mitochondria. T2DM is recognised as an inflammatory disease and glycation plays an important role. The frequent intake of sugary or starchy foods over time results in high glucose levels, which then stick to proteins in the blood and tissues in a process called glycation. This is somewhat like a slow biological version of caramelisation, where sugars react with proteins without enzymes. These altered proteins, known as advanced glycation end products (AGEs), can build up in tissues and bind to special receptors on cells called RAGE (Receptors for Advanced Glycation End Products).

Once activated, these receptors trigger a chain reaction: the release of oxidative molecules, the activation of inflammatory cytokines, and the recruitment of immune cells to the site.

Health authorities that urge populations to shift away from saturated fats have often failed to adequately assess the inflammatory potential of processed fats. Processed fats including industrial trans fats, hydrogenated oils, and refined seed oils commonly used in ultra-processed foods, are consistently associated with increased risk of cardiovascular disease, metabolic syndrome, and chronic inflammation. These fats frequently undergo chemical processing or high-heat treatment, generating harmful by-products that can disrupt lipid metabolism and impair endothelial function.

Context is important: saturated fats derived from heavily processed meats and packaged foods may confer greater risk than saturated fats from whole-food sources such as dairy and fresh meat. The role of high-quality, minimally processed fat sources in supporting metabolic health has been under-recognised in nutrition policy.[105] [106]

Low-grade systemic inflammation is increasingly recognised as a clinically relevant contributor to cardiovascular risk. High-sensitivity C-reactive protein (hsCRP) is a well-validated acute-phase inflammatory biomarker, synthesised by the liver in response to pro-inflammatory cytokines (notably interleukin-6). While hsCRP rises rapidly following acute infection or trauma, persistent elevation is thought to reflect ongoing low-grade inflammation. Elevated CRP concentrations are consistently associated with an increased risk of coronary heart disease and broader cardiovascular events.

Dietary patterns influence inflammatory status. Diets characterised by a high carbohydrate burden and a high intake of ultra-processed foods are associated with higher CRP concentrations, whereas low-carbohydrate dietary patterns are generally associated with reductions in CRP and other inflammatory markers. [107] [108] [109] [110] [111] In 2009, researchers developed and validated the Dietary Inflammatory Index (DII), demonstrating that shifts toward a more anti-inflammatory dietary pattern were associated with significant reductions in hs-CRP.[112]

In September 2025, the American College of Cardiology updated their guidance, with new ACC recommendations including universal screening of C-reactive protein levels in all patients.:

Measurement of hsCRP (>3 mg/L) can be used in routine clinical practice to identify primary prevention individuals at increased inflammatory risk as long as the patient is not acutely ill.[113]

Inflammation, as assessed by hsCRP, may not only be a more accurate predictor of risk for future cardiovascular events and death than hyperlipidaemia assessed by low-density lipoprotein cholesterol (LDLC), it may highlight risk in populations currently overlooked by standard screening approaches. Contemporary preventive cardiology frameworks, focussed on hypertension, dyslipidaemia, diabetes mellitus, and smoking, do not routinely account of the inflammatory status of the individual.[114]

Evidence from large population studies supports this position. A United Kingdom study, the largest analysis to date, involving 448,653 UK Biobank participants without known atherosclerotic cardiovascular disease, found that:

hsCRP independently enhances CV risk stratification, and the predictive performance of hsCRP was comparable to or greater than traditional risk factors such as systolic blood pressure or LDL-C.

…individuals with hsCRP levels >3 mg/L had a 34% higher risk of MACE, a 61% and 54% increased risk of CV death and all-cause death compared to those with hsCRP <1 mg/L.

Notably, ‘the association of hsCRP with all endpoints was consistent across subgroups.’[115] A separate U.K. cohort study investigating the usefulness of baseline serum hsCRP as a predictor of long-term cardiovascular events in stable patients with hypertension, found that participants in the top third of hsCRP experienced a substantially greater incidence of cardiovascular events and all-cause mortality, compared to the lowest third.[116]

Comparable findings have been reported in the U.S. In a prospective cohort study of 12,530 initially healthy women followed for 30 years, women with persistently elevated hsCRP concentrations had a significantly higher risk of future cardiovascular events, independent of traditional risk factors.[117]

Figure 3. Kurt B, Reugels M, Schneider KM, et al. (2025). C-reactive protein and cardiovascular risk in the general population. European Heart Journal.

In New Zealand, high-sensitivity CRP (hsCRP) is available, however, it is used more selectively, predominantly for cardiovascular risk stratification, and is not universally ordered. It may be requested by GPs or specialists, but it is not part of routine population screening in NZ.

HYPERINSULINAEMIA & INFLAMMATORY CASCADE – can precede obesity.

High refined carbohydrate intake.

Frequent intake of high-glycaemic carbs leads to large postprandial glucose spikes.
Pancreas releases large insulin pulses to bring glucose down.
No inflammation yet. Sets the hormonal scene (high insulin → low glucagon → low fat oxidation).
Sensitive individuals may show transient oxidative stress and low-grade inflammatory markers.

Chronically elevated insulin levels (hyperinsulinemia).

Even in normoglycaemia, insulin may remain elevated for hours.
Over time, tissues become less responsive → early insulin resistance.
Early signs of inflammation begin here: Chronic hyperinsulinemia suppresses autophagy (mTOR) and, together with hyperglycaemia/FFAs, increases ROS, altering immune cell signalling.
Acceleration of non-enzymatic glycation of circulating proteins.
Endothelial dysfunction and low-grade inflammation (e.g., IL-6, CRP) can precede fat gain.

Insulin promotes fat storage (visceral adiposity).

Inhibits lipolysis (fat breakdown) and stimulates lipogenesis (fat creation) in adipose tissue, especially visceral fat. Preferential deposition impacted by genetics, gender, stress etc.
Inflammation ramps up here. Repeated postprandial hyperglycaemia accelerates AGE formation; glycated proteins activate RAGE receptors, triggering NF-κB and downstream inflammatory cytokine release, which exacerbates tissue hypoxia.
Immune cells (esp. macrophages) infiltrate visceral fat. Adipose remains endocrine but becomes increasingly pro-inflammatory (from macrophage infiltration, cytokine.).
Macrophage infiltration reinforces adipose inflammation, amplifying insulin resistance.

Weight gain and metabolic inflexibility

Persistent hyperinsulinemia shifts caloric partitioning toward fat storage.
Appetite regulation can be disrupted via leptin and ghrelin and hypothalamic inflammation.
Ongoing inflammation fuels impaired mitochondrial function, exacerbates insulin resistance, and promotes hepatic steatosis (fatty liver).
Glycation accelerates in liver, muscle, and vascular tissues; AGEs crosslink extracellular matrix proteins, increasing vascular stiffness. Repeated postprandial hyperglycaemia accelerates glycation.
Immune cells in adipose and vessel walls respond with inflammatory amplification.

Obesity emerges & glycation drives inflammation — downstream of insulin load

Hyperinsulinemia precedes and drives weight gain in many individuals; obesity is often an outcome, not the origin. Especially in youth, where beta-cell resilience is limited.
Chronic exposure to glycation products increases oxidative stress, stiffens the vasculature, and damages renal filtration structures and pancreatic β-cells.
Inflammation is now systemic: -
– Endothelial cells, liver (via NAFLD), skeletal muscle (via lipotoxicity), kidney and β-cells.
– Adipose tissue macrophages release increase IL-6 levels, stimulating hepatic CRP production.

T2DM develops once beta-cell function falters

In youth, β-cell decline can be more rapid and often severe.
Persistent hyperglycaemia entrenches glycation, vascular injury, and chronic inflammation.
Glucotoxicity, lipotoxicity, and immune-mediated inflammation drive β-cell apoptosis and multi-organ complications (retinopathy, nephropathy, neuropathy, CVD).

While blood testing remains the conventional standard, urine and saliva present promising, less resource-intensive alternatives, especially for screening inflammatory markers in vulnerable populations, who may be reluctant or unable to undergo venipuncture.[118] [119]

People diagnosed with type 2 diabetes mellitus (T2DM) are substantially more likely to develop multiple co-existing conditions, and multimorbidity is the norm rather than the exception in this population. Increasingly, scientific research identifies a shared spectrum of upstream risk factors and overlapping pathophysiological pathways that drive the range of conditions commonly associated with a T2DM diagnosis.[120]

Glycation is thought to be a key contributor to the development of diabetes-related complications, contributing to the increased risk of multiple, overlapping health conditions. In parallel, recent meta-analyses and pooled evidence consistently demonstrate that elevated hsCRP is associated with an increased risk of incident type 2 diabetes and cardiometabolic events. The development of T2DM and cardiovascular disease share common inflammatory aetiologies, for which hsCRP serves as a well-validated biomarker. Elevated hsCRP concentrations are associated with a higher risk of both prediabetes and established T2DM.[121] [122] [123] [124]

Over time, this persistent low-grade inflammatory milieu, effectively captured by hsCRP, contributes to progressive microvascular damage, particularly affecting the eyes, kidneys, and peripheral nerves.[125] [126] [127] [128]

Without such an appreciation, guidelines may over-emphasise downstream correlates, such as obesity as a primary driver, and under-emphasise the contribution of the cumulative carbohydrate burden to elevated blood glucose, inflammation, insulin resistance and eventual diabetes.

Chapter 3. Brain Health: Consistently Associated With Metabolic Dysfunction.

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